1. Field of the Invention
The invention relates to a process for stabilizing cyclobutanone derivatives and also to correspondingly stabilized cyclobutanone derivatives.
2. Description of the Related Art
Cyclobutanone and its derivatives are an important reactant for some preparation processes of organic compounds. The preparation of cyclobutanone is known by different processes. For example, cyclobutanone, as described in DE 101 62 456, can be obtained by rearrangement of cyclopropylmethanol in aqueous solution in the presence of an acidic heterogeneous catalyst and subsequent dehydrogenation using a heterogeneous catalyst. A further process for preparing cyclobutanone is described by DE 199 10 464; in this process, the cyclobutanone is prepared by oxidizing cyclobutanol by means of alkali metal hypochlorite or alkaline earth metal hypochlorite.
The preparation of pure cyclobutanone represents a particular challenge, since the target product is generally contaminated by reactants and by secondary components which can form both in the course of preparation and through the storage of the cyclobutanone. For example, WO 2002/48083 A2 describes numerous compounds which are detectable as impurities in aqueous cyclobutanone. These impurities are frequently colored compounds, such that contaminated cyclobutanone can be recognized by its color. For example, Eastman describes, in WO 2002/48083 and also EP 1 180 509, a purification process for crude cyclobutanone over five process stages, such that cyclobutanone can be obtained in a purity of >90%.
In spite of this complicated purification process for cyclobutanone, a deposit forms in the cyclobutanone after a few days or a few months. This precipitate is very troublesome for the use of the cyclobutanone in numerous preparation processes. In order to reduce the formation of impurities, cyclobutanone is cooled and supplied in light-protected packaging. The mechanism of decomposition of cyclobutanone is described in some publications, as listed, for example, in WO 2002/48083.
Since cyclobutanone and its derivatives serve as synthetic units for active pharmaceutical ingredient synthesis, any prevention of by-products is desirable. First, the polymerization tendency of the cyclobutanone and second, the formation of by-products should be prevented. For example, WO 2002/48083 describes the addition of phenolic compounds to cyclobutanone and derivatives thereof, which are distributed homogeneously in the product, in order to prevent the formation of by-products by transport and storage. These phenolic compounds are the classical phenol-based stabilizers—so-called sterically hindered phenols, for example 2,6-di-tert-butyl-4-methylphenol, also known by the abbreviation BHT.
It is thus an object of the present invention to provide a process for stabilizing cyclobutanone derivatives. In particular, the stabilizer added should also be removable again from the cyclobutanone derivative, in order that the stabilizer itself does not cause problems in the further active pharmaceutical ingredient synthesis. Moreover, the stabilizer used should be non-toxic.